Oropharyngeal carcinoma (OPC) is a rare cancer with an age-adjusted incidence rate of 2.247 per 100,000 in the US in the year 2009. While smoking-related OPC are declining due to the reduction in tobacco use, the fraction of HPV-associated OPC appears to be increasing, by approximately 5% annually. Studies that have compared the molecular characteristics of HNSCC based on HPV status have demonstrated that compared to HPV-negative (smoking-related), HPV-positive tumors are characterized by low to the complete absence of TP53 gene mutations. Recent developments in genomic techniques have enabled the characterization of molecular alterations in singular detail. The Cancer Genome Atlas (TCGA) project presently includes 279 HNSCCs that have been characterized using DNA, RNA, and miRNA sequencing along with DNA copy number profiling, mRNA quantification, and methylation analysis. Though the largest effort of its kind, the consortia have identified important limitations in the number of oropharyngeal tumors (only 30 cases of 279), few cases classified as HPV-positive (only 34 of 279) and inadequate HPV characterization (based on P16 staining and other clinical parameters, and RNA-seq data). Although the TCGA analysis is planned to continue to 500 head and neck cancer cases, these limitations are likely to persist. Hence, further sequencing efforts are required in order to characterize the comprehensive landscape of somatic mutations in oropharyngeal carcinoma, and to improve our understanding of molecular heterogeneity based on viral involvement. This application aims to identify new driver mutations in oropharyngeal carcinoma, and to examine their association with HPV infection and outcome. We propose to sequence whole- exome of 100 pathologically confirmed oropharyngeal squamous cell carcinomas and their matched germline DNA. A recently developed in-house bioinformatics pipeline will be adapted for calling somatic and germline variants and filtering for potentially driver mutations in tumors. We will use the whole-exome sequencing data on oropharyngeal cancer from The Cancer Genome Atlas Project (TCGA) to replicate the identified genes of interest.